Pgf tetraols and alkanoyl esters

ABSTRACT

There are disclosed compounds of the formula:   WHEREIN Y is -CH2CH2- or trans-CH CH-, and both X and Z are CH2CH2-, or wherein Y is trans-CH CH-, X is cis-CH CH-, and Z is -CH2CH2- or cis-CH CH-, wherein R is hydrogen or lower alkanoyl, and wherein * indicates attachment of -OR to the ring in alpha or beta configuration. These novel compounds are useful for a variety of pharmacological purposes, including use as smooth muscle stimulants.

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[1 1.] 1W ,33'7 i451 0cc.3,11974 101811 TiETRAULS AND ALKANUYL ESTiZRS Inventors: Sunc Bergstrom; Jan Sjovail, both of Kemiska Institutioncn Karolinska Institutet, Stockholm 60, Sweden Filcd: Aug. 23., 1972 Appl. No: 282,952

Related ILLS, Application Data Continuation of Ser. No. 115,110, Feb. 12, 1971, abandoned, which is a continuationJn-part of Scr. No. 203,752, June 20, 1962, Pat. Nov 3598.858, which is a continuation-impart of Sen No. 199,209, April 9, 1962, abandoned, which is a continuutioiniirpzlrt of 581. No. 738,514, May 28, 1958, Pat. No. 3,069,322.

111* nrcign Application Priority Data Min, 29, 1962 Great Britain 12139/62 11.5%. C1 260/488 R, 260/410, 260/468 D, 260/514 D, 260/617 R, 424/311, 424/312, 424/343 lint. Q1... (10% 35/06, C070 69/20, C070 69/32 Field of Search 260/488 R, 617 R; 115/110 References Cited OTHER PUBLICATIONS Pabon ct 211., Rec. Tran. Chim, 85, 1251 (1966).

Primary Eraminer-Vivian Garner [57] ABSTRACT There are disclosed compounds of the formula:

27 Claims, N0 Drawings PGF TE'IRAOILS AND ALKANUYIL ESTEIIIS CROSS REFERENCE TO RELATED APPLICATIONS las I, II, III, IV, and V each have several centers of asymmetry. Formulas I, II, 'III, IV, and V are intended This application is a Continuation of Our COPending 5 to represent optically active compounds each with the 1 application Ser. No. 115,110, filed Feb. 12, 1971, now

DESCRIPTION OF THE INVENTION This invention relates to novel compositions of matter and is more specifically concerned with novel organic compounds of the formula:

no II on wherein Y is Cl-I CH or transCH=CH-, and both X and Z are Cl-I CH or wherein Y is transame absolute configuration as optically active prostaglandin E (PGE), later named prostaglandin E, (PGE and obtained from certain mammalian tissues, for example, sheep vesicular glands. See our said U.S.

Pat. No. 3,069,322. See also later publications, for example, Bergstrom et al., J. Biol. Chem. 238, 3555 (1963), Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and references cited in those.

In formulas I, II, III, IV, and V, a broken line attachment to the cyclopentane ring indicates a chain or group in alpha configuration, i.e., below the plane of the cyclopentane ring. A'heavy solid line attachment to the cyclopentane ring indicates a chain in beta configuration, i.e., above the plane of the cyclopentane ring.

The configuration of the side chain hydroxy in formulas I, II, III, IV, and V is S.

Systematic names for the compounds of Formula 11 wherein R is hydrogen are 4a- [7-hydroxyheptyl]-5B- ;[(3S)-3hydroxyoctyl]- l oz,3a-cyclopentanediol and 4- alcohol and dihydro-PGF, B alcohol, respectively.

Related systematic names are also available for the compounds of formulas III, IV, and V wherein the cis and trans unsaturation in those compounds is specified in the heptyl and octyl portions of the name. But for lower alkanoyl, and wherein indicates attachment of convenience hereinafter, the compounds of formula III -OR to the ring in alpha or beta configuration.

Included in formula I are alcohols (tetraols) and tet raalkanoates of the formulas:

III

wherein R is hydrogen are designated PGF, alcohol and PGF alcohol, the compounds of formula IV wherein R is hydrogen are designated PGF alcohol land PGF 5 alcohol, and the compounds of formula V wherein R is hydrogen are designated PGF alcohol and PGF alcohol, the a and ,B being assigned according to whether the hydroxy at the 3 position (see formula II numbering) is in alpha or beta configuration. As will subsequently appear, these PGF alcohol names 5 are based on the relation of these compounds to certain other compounds known as the prostaglandins F, e.g., PGF, ,1 or PGF, 5 which are carboxylic acids with COUII taking the place of the -CI-I OH in formula 111.

With regard to formulas I, II, III, IV, and V, examples of lower alkanoyl are alkanoyl of two to eight carbon atoms, inclusive, e.g., acetyl, propionyl, butyryl, valeryl, hexanoyl, heptanoyl, octanoyl, and branched chain isomeric forms of those, e.g., isobutyryl and isovaleryl.

The novel compounds of formulas I, II, III, IV, and V are potent in causing stimulation of smooth muscle as some physiological condition in mammals, including humans, useful domestic animals, pets, zoological specimens, and laboratory animals, for example, mice, rabbits, rats, and monkeys. For example, these compounds can be used to alleviate or prevent conditions of gastrointestinal atony in mammals, including humans, e.g., paralytic ileus following anesthesia and surgical operation or from other medical causes. For this purpose, the compound is administered parenterally, e.g., subcuta neously, intramuscularly or by intravenous injection or infusion in a dose range 0.1 to 2 mg. per kg. of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animals, and the frequency and route of administration. Small repeated doses are indicated when the aim is to prevent rather than alleviate the atony.

Another smooth muscle stimulatory area where these novel formula l, II, III, IV, and V compounds are useful is in the control or prevention of atonic uterine bleeding in mammals after abortion or delivery, to aid in the expulsion of the placenta, and during the puerperium. For this purpose, the compound is administered by intravenous infusion immediately after abortion or delivery at a dose in the range about 0.1 to about I ug;

per kg. of body weight per minute until the desired effeet is obtained. Subsequent doses are given by intravenous, subcutaneous, or intramuscular injection or infusion during puerperium in the range 0.1 to 2 mg. per kg. of body weight per day, again the exact dose depending on the age, weight, and condition of the patient or animal.

In still another smooth muscle stimulatory area, these novel compounds of formulas I, II, III, IV, and V are surprisingly useful in place of oxytocin to induce labor in pregnant female animals, including man, cows, sheep, and pigs, at or near term, or in pregnant animals with intrauterine death of the fetus from about weeks to term. For this purpose, the compound is infused intravenously at a dose of 0.1 to 100 ug. per kg. of body weight per minute until at or near the termination of the second stage of labor, i.e., expulsion of the fetus. These compounds are especially useful when the female is one or more weeks post-mature and natural labor has not started, or 12 to 60 hours after the membranes have ruptured and natural labor has not yet started. An alternative route of administration is oral.

The novel compounds of formulas I, II, III, IV, and V are also surprisingly useful for controlling the reproductive cycle in ovulating female mammals, including humans and animals such as monkeys, rats, rabbits, dogs, cattle, and the like. By the term ovulating female mammals is meant animals which are mature enough to ovulate but not so old that regular ovulation has ceased. For that purpose, PGF alcohol, for example, is administered systemically at a dose level in the range 0.1 mg. to about 20 mg. per kg. of body weight of the female mammal, advantageously during a span of time starting approximately at the time of ovulation and ending approximately at the time of menses or just prior to menses.- Intravaginal and intrauterine are alternative routes of administration. Additionally, expulsion of an embryo or a fetus is accomplished by similar administration of the compound during the first third of the normal mammalian gestation period.

The novel compounds of formulas I, II, III, IV, and V are also useful in mammals, including man, as nasal decongestants. For this purpose, the compounds are used in a dose range of about 10 rig. to about 10 mg. per ml. of a pharmacologically suitable liquid vehicle or as an aerosol spray, both for topical application.

The novel formula I, II, III, IV, and V compounds of this invention are used for the purposes described above in the alcohol form (tetraol form; Formulas I, II, III, IV, and V, all R=H) or in the tetraalkanoate form (all R=alkanoyl). When the tetraalkanoate form is used, the alkanoyl moiety is any of those within the definition of R. However, acetyl is especially preferred for optimum absorption by the body or experimental animal system. In formulas I, II, III, IV, and V, it is intended that all R be hydrogen or that all be alkanoyl.

When the novel formula I, II, III, IV, and V compounds are used for intravenous injection or infusion, sterile aqueous isotonic solutions are preferred. For that purpose, it is preferred because of increased water solubility that R in formula I, II, III, IV, and V be hydrogen. For subcutaneous or intramuscular injection, sterile solutions or suspensions of the tetraol or tetraalkanoate in aqueous or non-aqueous media are used. Tablets, capsules, and liquid preparations such as syrups, elixers, and simple solutions, with the usual pharmaceutical carriers, are used for oral or sublingual administration. For rectal, vaginal, or intrauterine administration, suppositories, lavage and douche preparations, and solutions as such or contained in a sponge, all prepared by methods known in the art, are used.

The compound known as PGF a or one of its alkyl esters, e.g., the methyl ester, is used as a reactant to prepare PGF alcohol (formula III, R=H, =alpha). Similarly, the compound known as PGF or one of its alkyl esters, e.g., the methyl ester, is used as a reactant to prepare PGF alcohol (formula III, R==I-I, =beta). The formulas of PGF (VI) and PGF (VII) are as follows:

IIO

, vyvv IIO '11 on y H0 on The formulas of dihydro-PGF, B PGF and PGF B are the same as for Vlll, IX, and X except that the upper ring hydroxy is in beta configuration rather than alpha configuration as shown in those formulas (compare formula VI and formula Vll).

DihydroPGF, a dihydro-PGF, PGF, 0: PGF, PGF a PGF B ,PGF ,PGF ,and their alkyl esters, e.g., their methyl esters, are prepared as described in our said U.S. Pat. No. 3,069,322 or in our said copending application Ser. No. 203,752.

These transformations involve the change of the COOH or COOR wherein R is alkyl, e.g., methyl, of one of these PGF reactants to CH OH. That change is accomplished by reacting the PGF reactant with any of the reagents known to effect that sort of change without at the same time saturating the olefmic unsaturation present in some of these PGF reactants. An especially preferred reagent for this purpose is lithium aluminum hydride. Procedures for using this reagent to effect this transformation are described below in the Examples.

When a tetraalltanoate of one of the formula 1, 11, 111, IV, or V PGF alcohols (all R= alkanoyl) is desired for one of the above-described pharmacological purposes, it is prepared by reacting the corresponding tetrahydroxy compounds, i.e., all R=hydrogen, with an alkanoic anhydride corresponding to an alkanoic acid of two to eight carbon atoms, inclusive. Examples of these anhydrides are acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, hexanoic anhydride, heptanoic anhydride, octanoic anhydride, and isomeric forms of those.

This reaction leading to these tetraalkanoates is advantageously carried out by mixing the hydroxy compound and the acid anhydride, preferably in the presence of a tertiary amine such as pyridine or triethylamine. A substantial excess of the anhydride is used, preferably about 10 to 10,000 moles of anhydride per mole of the hydroxy compound reactant. The excess anhy dride serves as a reaction diluent and solvent. An inert organic diluent, for example, dioxane, can also be added. It is preferred to use enough of the tertiary amine to neutralize the carboxylic acid produced by the reaction.

The reaction is preferably carried out in the range about 0 to about C. The necessary reaction time will depend on such factors as the reaction temperature, and the nature of the anhydride and tertiary amine reactants. With acetic anhydride, pyridine, and a 25 C. reaction temperature, a 12 to 24-hour reaction time is used.

The desired tetraalkanoate is isolated from the reaction mixture by conventional methods. For example, the excess anhydride is decomposed with water, and the resulting mixture acidified and then extracted with a solvent such as diethyl ether. The desired tetraalkanoate is recovered from the diethyl ether extract by evaporation. The tetraalkanoate is then purified by conventional methods, advantageously by chromatography.

The invention can be more fully understood by the following examples.

EXAMPLE 1 PGF a Alcohol To 1.2 mg. of lithium aluminum hydride in 10 ml. of absolute either there is added a solution of 3.6 mg. of PGF in 1 ml. of redistilled dry tetrahydrofuran. After the mixture is stirred for 2 hours at room temperature, the excess lithium aluminum hydride is decomposed by addition of 0.5 ml. of 4 per cent aqueous ammonium chloride. The mixture is filtered and the layers are separated. The aqueous layer is washed three times with 2 ml. each of ether. The combined organic phases are washed once with 2 ml. of saturated sodium chloride solution, dried over sodium sulfate, and evaporated to give PGFZ or alcohol. If desired, this product residue is further purified by vapor phase chromatography, partition chromatography, and crystallization from ether-hexane to give the same material,

EXAMPLE 2 PGF Alcohol A solution of PGF, 0: methyl ester (275 mg.) in 20 ml. of benzene is added to a stirred suspension of lithium aluminum hydride (1.0 g.) in a mixture of dry diethyl ether (50 ml.) and benzene (10 ml.) in an atmosphere of nitrogen gas. This mixture is stirred 2 hours at 25 C., and is then heated and stirred at reflux for 1.5 hours. The reaction mixture is cooled, and the excess lithium aluminum hydride is decomposed by the successive addition of ethyl acetate and water. The solution is filtered, dried with sodium sulfate, and evaporated under reduced pressure. The residue is crystallized from methylene chloride to give 150 mg. PGF, a alcohol; m.p. l00l06 C. Recrystallization from a mixture of methanol and ethyl acetate gives the same product; m.p. "108 C; infrared absorption (mineral oil mull) at 3280, 1665, 1130, 1080, 1060, 1020, and 965 cm.

EXAMPLE 3' lPGl B Alcohol Following the procedure of Example 1 or Example 2, PGF, 3 and PGF 5 methyl ester are transformed to PGF 3 alcohol.

EXAMPLE 4 PGF 5 Alcohol Following the procedure of Example 1 or Example 2, PGF B and PGF 3 methyl ester are transformed to PGF 3 alcohol.

EXAMPLE 5 PGF Alcohol Following the procedure of Example 1 or Example 2, PGF a and PGF methyl ester are transformed to PGF alcohol.

EXAMPLE 6 PGF;, 5 Alcohol Following the procedure of Example 1 or Example 2,

FOR, 3 and PGF;, methyl ester are transformed to PGF3 alcohol.

EXAMPLE 7 Dihydro-PGF, Alcohol Following the procedure of Example 1 or Example 2, dihydro-PGF and dihydro-PGF methyl ester are transformed to dihydroPGF alcohol.

EXAMPLE 8 Dihydro-PGF Alcohol Following the procedure of Example I or Example 2, dihydro-PGF; and dihydro-PGF methyl ester are transformed to dihydro-PGF, B alcohol.

EXAMPLE 9 PGF Alcohol Tetraacetate To 1 mg. of PGF alcohol in 0.1 ml. of pyridine is added 0.1 ml. of acetic anhydride. The solution is kept under nitrogen for 4 hours at room temperature, is diluted with water, and after one-half hour, extracted with ether. The ether solution is washed successively with water, dilute hydrochloric acid, dilute sodium bicarbonate, water, and then dried over anhydrous sodium sulfate. The solution is evaporated to give the tetraacetate of PGF alcohol.

Following the procedure of Example 9, dihydro- PGF alcohol, dihydro-PGF, B alcohol, PGF alcohol, PGF B alcohol, PGF alcohol, PGF alcohol, and PGF alcohol are each transformed to tetraacetates.

Also following the procedure of Example 9 but using propionic anhydride, isobutyric anhydride, and hexanoic anhydride each in place of the acetic anhydride, there are obtained the tetrapropionate, tetraisobutyrate, and tetrahexanoate of PGF alcohol. in the same manner, the tetrapropionates, tetraisobutyrates, and tetrahexanoates of dihydro-PGF, a alcohol, dihydro-PGF B alcohol, PGF, (1 alcohol, PGF, 5 alcohol, PGF B alcohol, PGF alcohol, and PGE, 5 alcohol are prepared.

We claim:

1. A compound of the formula:

wherein Y is CH CH or transCH=l-l, and both X and Z are -CH CH or wherein Y is tran-- sCH=CH-, X is cisCH=CH-, and Z is CH C- H or cisCl-l=CH, wherein R is hydrogen or lower alkanoyl, all R groups being the same, and wherein indicates attachment of OR to the ring in alpha or beta configuration.

2. A compound according to claim ll wherein indicates an alpha attachment of ()R to the ring.

3. A compound according to claim 1 wherein indicates a beta attachment of OR to the ring.

4. A compound according to claim 2 wherein X, Y, and Z are CH CH 5. A compound according to claim l wherein all R are hydrogen.

6. A compound according to claim 4 wherein all R are acetyl.

7. A compound according to claim 2 wherein Y is trans-CH=CH-, and X and Y are --CH CH 8. A compound according to claim 7 wherein all R are hydrogen.

9. A compound according to claim 7 wherein all R are acetyl.

10. A compound according to claim 2 wherein Y is transCH=CH-, X is cisCH=CH-, and Z is '-CH2CH2.

11. A compound according to claim 10 wherein all R are hydrogen.

12. A compound according to claim 10 wherein all R are acetyl.

13. A compound according to claim 2 wherein Y is trans-CH=CH, and X and Z are cis'CH=CH-.

M. A compound according to claim 13 wherein all R are hydrogen.

15. A compound according to claim l3 wherein all R are acetyl.

16. A compound according to claim 3 wherein X, Y, and Z are -CH CH 17. A compound according to claim 16 wherein all R are hydrogen.

l8. A compound according to claim 16 wherein all R are acetyl.

19. A compound according to claim 3 wherein Y is transCll=-CH, and X and Z are CH CH 20. A compound according to claim 19 wherein all R are hydrogen.

21. A compound according to claim 19 wherein all R are acetyl.

22. A compound according to claim 3 wherein Y is trans-CH=CH, X is cisCH=Cl'l-, and Z is CH CH 2.3. A compound according to claim 22 wherein all R are hydrogen.

24. A compound according to claim 22 wherein all R are acetyl.

25. A compound according to claim 31 wherein Y is trans-CH=CH, and X and Z are cisCl-l=CH.

26. A compound according to claim 25 wherein all R are hydrogen.

27. A compound according to claim 25 wherein all R are acetyl. 

1. A COMPOUND OF THE FORMULA:
 2. A compound according to claim 1 wherein * indicates an alpha attachment of -OR to the ring.
 3. A compound according to claim 1 wherein * indicates a beta attachment of -OR to the ring.
 4. A compound according to claim 2 wherein X, Y, and Z are -CH2CH2-.
 5. A compound according to claim 4 wherein all R are hydrogen.
 6. A compound according to claim 4 wherein all R are acetyl.
 7. A compound according to claim 2 wherein Y is trans-CH CH-, and X and Y are -CH2CH2-.
 8. A compound according to claim 7 wherein all R are hydrogen.
 9. A compound according to claim 7 wherein all R are acetyl.
 10. A compound according to claim 2 wherein Y is trans-CH CH-, X is cis-CH CH-, and Z is -CH2CH2-.
 11. A compound according to claim 10 wherein all R are hydrogen.
 12. A compound according to claim 10 wherein all R are acetyl.
 13. A compound according to claim 2 wherein Y is trans-CH CH-, and X and Z are cis-CH CH-.
 14. A compound according to claim 13 wherein all R are hydrogen.
 15. A compound according to claim 13 wherein all R are acetyl.
 16. A compound according to claim 3 wherein X, Y, and Z are -CH2CH2-.
 17. A compound according to claim 16 wherein all R are hydrogen.
 18. A compound according to claim 16 wherein all R are acetyl.
 19. A compound according to claim 3 wherein Y is trans-CH CH-, and X and Z are -CH2CH2-.
 20. A compound according to claim 19 wherein all R are hydrogen.
 21. A compound according to claim 19 wherein all R are acetyl.
 22. A compound according to claim 3 wherein Y is trans-CH CH-, X is cis-CH CH-, and Z is -CH2CH2-.
 23. A compound according to claim 22 wherein all R are hydrogen.
 24. A compound according to claim 22 wherein all R are acetyl.
 25. A compound according to claim 3 wherein Y is trans-CH CH-, and X and Z are cis-CH CH-.
 26. A compound according to claim 25 wherein all R are hydrogen.
 27. A compound according to claim 25 wherein all R are acetyl. 